1. Field of the Invention
The present invention relates to cinnamaldehyde derivatives represented by formula 1, process for preparation and pharmaceutical compositions thereof. Particularly, the present invention relates to cinnamaldehyde derivatives inhibiting growth of tumor cell and regulating cell cycle, the method for preparation thereof and the pharmaceutical composition as tumor cell growth inhibitor or cell cycle regulator. 
(wherein, R1, R1′, R2, R2′, R3 and R3′ are described in the below.)
2. Description of the Prior Art
Proliferation, differentiation and apoptosis are the major phenomena to keep a life. In order for cell to function normally, cellular proliferation, differentiation, and apoptosis are regulated by an elaborate intracellular and intercellular signal transduction system. That is, once cells are given a signal from outside, the signal is transferred to cellular clock by signaling proteins (PLC, PKC, Shc, Grb2, Raf, MAPK, MEK, etc.) and signaling messengers (GTP, cAMP, etc.). Any abnormality in the process causes diseases such as cancer.
Cell cycle is composed of following stages; Gap(G1), DNA synthesis(S), Gap2(G2) and Meiosis(M). In addition to the stages, when cells have been under the condition of having lower concentration of a growth factor for a long while, the cells get into the resting stage(Go), in which cell growth is stopped.
In cell cycle, a very complicated network, so called ‘check point’, makes the cell clock move properly in the order of G1-S-G2-M. The obstruction of the regulating mechanism of the check point results in uncontrolled cell growth.
If signal transduction from outside of the nucleus is smooth and nutritional condition is good, cells become larger in stage G1 and then entered cell cycle. Cell cycle goes into action in G1 check point which is named as start point in yeast cells, and restriction point in mammalian cells. After passing through the stage, if there is no specific obstruction, cells go through the 4 stages automatically, leading to the replication of genomes and differentiation. The procedure, especially in mammalian cells, is precisely explained hereinafter. The stage G1 having the check point is a preparatory stage for making new cells. At this time, enough growth factors and nutrition should be given to cells. Otherwise, cell cycle is stopped and cells go into the stage Go with no more growth. However, cell cycle progresses to the stage S under the supply of various growth factors and nutrition. At this time, replication of genome is carried out, two copies of chromosomes are produced, and various factors in cytoplasm are duplicated as well in order for a cell to be differentiated into two individual cells. After passing through the stage S, cells go into the stage G2, which can be said as the second check point. During the stage G2, DNA replication is regulated and completed, and entry to meiosis (M stage) is prepared. Lots of factors essential for the construction of a cell are generated in this stage. After the generation of all the required factors for the cell division, cells progress to the stage M, the stage in which actual cell proliferation occurs. The stage M has the shortest period among stages. In this stage, the duplicated genome is separated and each part moves to both poles, resulting in two daughter cells. All the stages are required in order for a cell to divide into two cells, so that they are very important for continuing the life of a cell. Thus, the studies on cell cycle and the development of a regulator of the cell cycle are prerequisite for the studies on mechanisms of cell growth and for the development of a preventive or a treatment agent for cancer caused by the abnormality of cell cycle (Nature Review Cancer, 2001, 1, 222-231).
As mentioned above, mammalian cell growth can be regulated by controlling the first check point in G1 stage or the second check point in G2/M stage. The abnormal progress of the first or the second check point is involved in cellular ageing or the development of cancer. And cycline D (D1, D2, D3, etc.) plays an important role in those check points. Cycline D regulates the enzyme activity by being combined with cycline dependant kinases (CDK; CDK2, CDK4, CDK6), and is also deeply involved in the regulation of whole cell cycle by CDC25 which functions to remove phosphate group of a phosphorylated protein. Based on that founding, it is no wonder that various cell cycle regulators have been good candidates for the development of a treatment agent for intractable diseases such as cancers. (Current Opinion in Chemical Biology, 2002, 6, 472-278).
Thus, the present inventors have disclosed that the novel cinnamaldehyde derivatives could block the G2/M selectively and have completed the invention by confirming that the cinnamaldehyde derivatives could be effectively used as a cell cycle regulator and as an inhibitor for abnormal cell growth of cancer cells.